Substance P plays critical roles in itch and neurogenic inflammation. This neuropeptide has been thought to mediate its actions via the NK1 receptor. Unexpectedly, we have found that substance P is a potent agonist of human MrgX2 and mouse MrgA1, homologous members of the Mrgpr family of receptors that been linked strongly to itch and nociception. SP-evoked scratching is reduced to baseline in Mrg knockout mice. We hypothesize that human MrgprX2 and mouse MrgprA1 play critical roles in SP-induced itch. Evaluating this hypothesis has the potential to be transformative by providing new insights into understanding the basic mechanisms of itch while identifying therapeutic targets leading to new medications for those who suffer from itch.